The goal of this R21/R33 computational and software project proposal is to support the parallel R21/R33 experimental project. The long-term goal of these two R21/R33 projects is to demonstrate a novel nanotechnology concept that we developed at Oak Ridge National Laboratory for rapid nanoscale reading of nucleic acid sequences directly on an individual molecule. According to this concept, the genetic sequence information can be obtained by scanning a DNA molecule base by base at a nanometer scale as if one were looking through a strip of movie film. The proposed nanotechnology has the potential capability of performing DNA sequencing at a speed that is at least about 2800 times faster than that of the current technology. This enhanced performance is made possible by a series of innovations, including novel applications of a fine-tuned nanometer gap for passage of a single DNA molecule, thin-layer microfluidics for sample loading and delivery, programmable electric fields for precise control of DNA movement, and detection of DNA nucleotide bases by nanoelectrode-gated tunneling conductance measurements. During the R21 pilot phase (the first two years) of this computational project, we will perform quantum-mechanical computations to provide better understanding of the nanoelectrode-gated electron-tunneling nucleotide detection process and apply molecular dynamics simulations to compute the needed electric fields to effectively drive and control the transport and conformational motion of a DNA chain through the detection gate. We will also develop a key software that will be employed by the experimental project at the beginning of the R33 phase for the system assembly and control. When these and the key R21 milestone of the experimental project (demonstration of nanoelectrode-gated nucleotide detection) are achieved to the satisfaction of NIH, this project may then move onto the R33 phase to further support the experimental project and fully develop and demonstrate this novel nanotechnology for rapid DNA sequencing by nanoscale direct reading on single DNA molecules. This (R21/R33) project proposal is in response to NIH RFA-HG-04-003 program announcement for Revolutionary Genome Sequencing Technologies. [unreadable] [unreadable]